ABSTRACT
Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. We addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom. Key steps in the synthesis include a Meyer-Schuster/Nazarov cascade, a hypoiodite mediated oxyfunctionalization, and the late-stage installation of a hydroxyl group on the C-ring of the steroid.
Subject(s)
Biological Products , Molecular Structure , Biological Products/chemistry , Biological Products/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Steroids/chemistry , Steroids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacologyABSTRACT
Twelve spiro thiazolidinone compounds (A-L) were synthesized via either conventional thermal or ultrasonication techniques using Fe2O3 nanoparticles. The modification of the traditional procedure by using Fe2O3 nanoparticles led to enhancement of the yield of the desired candidates to 78-93% in approximately half reaction time compared with 58-79% without catalyst. The products were fully characterized using different analytical and spectroscopic techniques. The structure of the two derivatives 4-phenyl-1-thia-4-azaspirodecan-3-one (A) and 4-(p-tolyl)-1-thia-4-azaspirodecan-3-one (B) were also determined using single crystal X-ray diffraction and Hirshfeld surface analysis. The two compounds (A and B) were crystallized in the orthorhombic system with Pbca and P212121 space groups, respectively. In addition, the crystal packing of compounds revealed the formation of supramolecular array with a net of intermolecular hydrogen bonding interactions. The energy optimized geometries of some selected derivatives were performed by density functional theory (DFT/B3LYP). The reactivity descriptors were also calculated and correlated with their biological properties. All the reported compounds were screened for antimicrobial inhibitions. The two derivatives, F and J, exhibited the highest levels of bacterial inhibition with an inhibition zone of 10-17 mm. Also, the two derivatives, F and J, displayed the most potent fungal inhibition with an inhibition zone of 15-23 mm. Molecular docking investigations of some selected derivatives were performed using a B-DNA (PDB: 1BNA) as a macromolecular target. Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial activities and the computed reactivity parameters.
Subject(s)
Molecular Docking Simulation , Thiazolidines , Catalysis , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Crystallography, X-Ray/methods , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Density Functional Theory , Microbial Sensitivity Tests , Ferric Compounds/chemistry , Hydrogen BondingABSTRACT
A series of 21 new 7'H-spiro[azetidine-3,5'-furo [3,4-d]pyrimidine]s substituted at the pyrimidine ring second position were synthesized. The compounds showed high antibacterial in vitro activity against M. tuberculosis. Two compounds had lower minimum inhibitory concentrations against Mtb (H37Rv strain) compared with isoniazid. The novel spirocyclic scaffold shows excellent properties for anti-tuberculosis drug development.
Subject(s)
Antitubercular Agents , Azetidines , Microbial Sensitivity Tests , Mycobacterium tuberculosis , Nitrofurans , Spiro Compounds , Mycobacterium tuberculosis/drug effects , Antitubercular Agents/pharmacology , Antitubercular Agents/chemistry , Antitubercular Agents/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Nitrofurans/pharmacology , Nitrofurans/chemistry , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Molecular StructureABSTRACT
This review describes novel organocatalytic methods for the enantioselective construction of spiroindans and spirochromans and the application of the methods to the total synthesis of natural products. We developed an intramolecular Friedel-Craftstype 1,4-addition in which the substrates were a resorcinol derivative and 2-cyclohexenone linked by an alkyl chain. The reaction proceeded smoothly in the presence of a cinchonidine-based primary amine (30 mol%) with water and p-bromophenol as additives. A variety of spiroindanes were obtained with high enantioselectivity under these conditions. The reaction was applied in the first total synthesis of the unusual proaporphine alkaloid (-)-misramine, which included the key steps of enantioselective spirocyclization and double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. The total synthesis of misrametine was achieved by selective demethylation of the methoxy group from the precursor to misramine. Next, a method for highly enantioselective organocatalytic construction of spirochromans containing a tetrasubstituted stereocenter was developed. An intramolecular oxy-Michael addition was catalyzed by a bifunctional cinchona alkaloid thiourea catalyst. A variety of spirochroman compounds containing a tetrasubstituted stereocenter were obtained with excellent enantioselectivity of up to 99% enantiomeric excess. The reaction was applied to the asymmetric formal synthesis of (-)-(R)-cordiachromene.
Subject(s)
Biological Products , Catalysis , Biological Products/chemical synthesis , Biological Products/chemistry , Stereoisomerism , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Cinchona Alkaloids/chemistry , Cyclohexanones/chemical synthesis , Cyclohexanones/chemistry , Organic Chemistry Phenomena , Pharmaceutical Preparations/chemical synthesis , Pharmaceutical Preparations/chemistry , Amines/chemistry , Amines/chemical synthesis , Thiourea/chemistry , Thiourea/chemical synthesis , Resorcinols/chemical synthesis , Resorcinols/chemistry , Indans/chemical synthesis , Indans/chemistryABSTRACT
A novel series of 5'-benzylidene-3'-phenylspiro[indoline-3,2'-thiazolidine]-2,4'(1H)-diones 6a-d and spiro[indoline-3,2'-thiazolo[5,4-e]pyrimido[1,2-a]pyrimidin]-2(1H)-one 9a-d derivatives have been synthesized. All the newly synthesized compounds were evaluated for antifungal and anti-candidiasis activity by using Disc Diffusion and Modified Microdilution methods. The antimicrobial experiments have shown that the synthesized compounds demonstrated broad-spectrum antifungal activity in vitro. Among them, compounds 9a-9d had stronger antifungal activity against Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans; compounds 6a-d also showed significant antifungal activity against selected fungal strains as compared to ketoconazole, the reference antifungal drug. The evaluation of antifungal activity against drug-resistant fungal variants showed that the designed compounds had significant antifungal activity against the tested variants. The combination of compounds (6a-d) and (9a-d) exhibited that the synthesized compounds had synergistic effects or additive effects. These results demonstrated that the synthesized compounds were putative chitin synthase inhibitors exhibiting broad spectrum antifungal activities. The present results indicate that novel spiro pyrimidine derivatives can be used as an active pharmaceutical ingredient for novel drug candidate for treatment of dermatophytosis and other fungal agents.
Subject(s)
Antifungal Agents , Arthrodermataceae , Candida albicans , Pyrimidines , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/chemical synthesis , Candida albicans/drug effects , Pyrimidines/pharmacology , Pyrimidines/chemistry , Pyrimidines/chemical synthesis , Arthrodermataceae/drug effects , Microbial Sensitivity Tests , Spiro Compounds/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Trichophyton/drug effects , HumansABSTRACT
We have devised a supported-amine-catalyzed efficient synthesis of spiro-thiazolone-tetrahydrothiophenes via a sulfa-Michael/aldol cascade approach. The catalyst demonstrated sustained efficacy over 21 cycles. These derivatives were found to exhibit excellent binding abilities with purified human serum albumin as indicated by both in silico and in vitro-based experiments.
Subject(s)
Amines , Thiophenes , Humans , Catalysis , Thiophenes/chemistry , Thiophenes/chemical synthesis , Amines/chemistry , Amines/chemical synthesis , Serum Albumin, Human/chemistry , Serum Albumin, Human/metabolism , Protein Binding , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Molecular Structure , Thiazoles/chemistry , Thiazoles/chemical synthesis , Molecular Docking SimulationABSTRACT
Spirotryprostatins are representative members of medicinally interesting bioactive molecules of the spirooxindole natural products. In this communication, we present a novel enantioselective total synthesis of the spirooxindole alkaloid dihydrospirotryprostatin B. The synthesis takes advantage of copper-catalyzed tandem reaction of o-iodoanilide chiral sulfinamide derivatives with alkynone to rapidly construct the key quaternary carbon stereocenter of the natural product dihydrospirotryprostatin B.
Subject(s)
Spiro Compounds , Stereoisomerism , Molecular Structure , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Biological Products/chemical synthesis , Biological Products/chemistry , Catalysis , Copper/chemistry , Alkaloids/chemical synthesis , Alkaloids/chemistryABSTRACT
We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.
Subject(s)
Drug Design , HIV Integrase Inhibitors , HIV Integrase , HIV-1 , Spiro Compounds , HIV Integrase Inhibitors/pharmacology , HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/chemistry , HIV Integrase/metabolism , HIV-1/drug effects , Crystallography, X-Ray , Rats , Structure-Activity Relationship , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Animals , Humans , Allosteric Regulation/drug effects , Molecular Structure , Models, Molecular , Binding SitesABSTRACT
The cluster of four skipped exo-methylene substituents on the "northern" wing of limaol renders this dinoflagellate-derived marine natural product unique in structural terms. This arguably non-thermodynamic array gains kinetic stability by virtue of populating local conformations which impede isomerization to a partly or fully conjugated polyene. This analysis suggested that the difficulties encountered during the late stages of our first total synthesis of this polyketide had not been caused by an overly fragile character of this unusual substructure; rather, an unfavorable steric microenvironment about the spirotricyclic core was identified as the likely cause. To remedy the issue, the protecting groups on this central fragment were changed; in effect, this amendment allowed all strategic and practical problems to be addressed. As a result, the overall yield over the longest linear sequence was multiplied by a factor of almost five and the material throughput increased more than eighty-fold per run. Key-to-success was a gold-catalyzed spirocyclization reaction; the reasons why a Brønsted acid cocatalyst is needed and the origin of the excellent levels of selectivity were delineated. The change of the protecting groups also allowed for much improved fragment coupling processes; most notably, the sequence of a substrate-controlled carbonyl addition reaction followed by Mitsunobu inversion that had originally been necessary to affix the southern tail to the core could be replaced by a reagent controlled asymmetric allylation. Finally, a much-improved route to the "northern" sector was established by leveraging the power of asymmetric hydrogenation of a 2-pyrone derivative. Limaol was found to combine appreciable antiparasitic activity with very modest cytotoxicity.
Subject(s)
Polyketides , Polyketides/chemistry , Polyketides/chemical synthesis , Polyketides/pharmacology , Catalysis , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Antiparasitic Agents/chemical synthesis , Gold/chemistry , Biological Products/chemistry , Biological Products/chemical synthesis , Biological Products/pharmacology , Dinoflagellida/chemistry , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Cyclization , Animals , StereoisomerismABSTRACT
Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure-activity relationship (SAR) systematically studied through design, syntheses, and in vivo characterization of 24 analogues. Two analogues, 21 and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivo effects primarily mediated by KOR and DOR, penetrated the blood-brain barrier, and did not function as reinforcers. Additionally, 21 produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.
Subject(s)
Morphinans , Spiro Compounds , Structure-Activity Relationship , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Animals , Morphinans/pharmacology , Morphinans/chemistry , Morphinans/chemical synthesis , Morphinans/therapeutic use , Mice , Male , Humans , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/metabolism , Pain Management/methods , Pain/drug therapy , Analgesics/pharmacology , Analgesics/chemistry , Analgesics/chemical synthesis , Analgesics/therapeutic useABSTRACT
Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.
Subject(s)
Alkaloids , Alzheimer Disease , Spiro Compounds , Stereoisomerism , Alzheimer Disease/drug therapy , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Alkaloids/chemistry , Alkaloids/chemical synthesis , Alkaloids/pharmacology , Molecular Structure , Benzofurans/chemistry , Benzofurans/chemical synthesis , Benzofurans/pharmacologyABSTRACT
Environment-benign, multicomponent synthetic methodologies are vital in modern pharmaceutical research and facilitates multi-targeted drug development via synergistic approach. Herein, we reported green and efficient synthesis of pyrano[2,3-c]pyrazole fused spirooxindole linked 1,2,3-triazoles using a tea waste supported copper catalyst (TWCu). The synthetic approach involves a one-pot, five-component reaction using N-propargylated isatin, hydrazine hydrate, ethyl acetoacetate, malononitrile/ethyl cyanoacetate and aryl azides as model substrates. Mechanistically, the reaction was found to proceed via in situ pyrazolone formation followed by Knoevenagel condensation, azide alkyne cycloaddition and Michael's addition reactions. The molecules were developed using structure-based drug design. The primary goal is to identifying anti-oxidant molecules with potential ability to modulate α-amylase and DPP4 (dipeptidyl-peptidase 4) activity. The anti-oxidant analysis, as determined via DPPH, suggested that the synthesized compounds, A6 and A10 possessed excellent anti-oxidant potential compared to butylated hydroxytoluene (BHT). In contrast, compounds A3, A5, A8, A9, A13, A15, and A18 were found to possess comparable anti-oxidant potential. Among these, A3 and A13 possessed potential α-amylase inhibitory activity compared to the acarbose, and A3 further emerged as dual inhibitors of both DPP4 and α-amylase with anti-oxidant potential. The relationship of functionalities on their anti-oxidant and enzymatic inhibition was explored in context to their SAR that was further corroborated using in silico techniques and enzyme kinetics.
Subject(s)
Antioxidants , Dipeptidyl Peptidase 4 , Hypoglycemic Agents , Pyrazoles , Triazoles , alpha-Amylases , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/chemical synthesis , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology , Triazoles/chemical synthesis , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemical synthesis , Structure-Activity Relationship , alpha-Amylases/antagonists & inhibitors , alpha-Amylases/metabolism , Dipeptidyl Peptidase 4/metabolism , Molecular Structure , Humans , Dose-Response Relationship, Drug , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Molecular Docking Simulation , Picrates/antagonists & inhibitors , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Oxindoles/pharmacology , Oxindoles/chemistry , Oxindoles/chemical synthesis , Benzopyrans , NitrilesABSTRACT
Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.
Subject(s)
Acute Lung Injury , Carbazoles , Drug Design , Nucleotidyltransferases , Pyrrolidines , Acute Lung Injury/drug therapy , Animals , Mice , Male , Humans , Rats , Carbazoles/chemical synthesis , Carbazoles/pharmacology , Carbazoles/chemistry , Carbazoles/therapeutic use , Carbazoles/pharmacokinetics , Pyrrolidines/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/chemistry , Pyrrolidines/therapeutic use , Pyrrolidines/pharmacokinetics , Nucleotidyltransferases/antagonists & inhibitors , Nucleotidyltransferases/metabolism , Lipopolysaccharides , Rats, Sprague-Dawley , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/therapeutic use , Spiro Compounds/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/chemistry , Structure-Activity Relationship , Molecular Docking SimulationABSTRACT
Synthesis of the A/D/E-ring core compounds of maoecrystal V was achieved. The key Diels-Alder reactions between tricyclic α-methylene lactones and Kitahara-Danishefsky dienes afforded the spirocyclic core compounds in a regioselective and stereoselective manner.
Subject(s)
Lactones , Stereoisomerism , Lactones/chemistry , Lactones/chemical synthesis , Cycloaddition Reaction , Chemistry Techniques, Synthetic , Diterpenes/chemical synthesis , Diterpenes/chemistry , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Molecular StructureABSTRACT
FR901464 is a natural product that exhibits antiproliferative activity at single-digit nanomolar concentrations in cancer cells. Its tetrahydropyran-spiroepoxide covalently binds the spliceosome. Through our medicinal chemistry campaign, we serendipitously discovered that a bromoetherification formed a tetrahydrofuran. The tetrahydrofuran analog was three orders of magnitude less potent than the corresponding tetrahydropyran analogs. This study shows the significance of the tetrahydropyran ring that presents the epoxide toward the spliceosome.
Subject(s)
Epoxy Compounds , Furans , Pyrans , Spiro Compounds , Humans , Cell Line, Tumor , Epoxy Compounds/chemical synthesis , Epoxy Compounds/pharmacology , Furans/chemical synthesis , Furans/pharmacology , Pyrans/chemical synthesis , Pyrans/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacologyABSTRACT
A water mediated three-component reaction of isatin, 4-aminocoumarin, and 1,3-cyclodicarbonyl compounds is reported for the synthesis of spiro[chromeno[4,3-b]cyclopenta[e]pyridine-7,3'-indoline]trione and the spiro[chromeno[4,3-b]quinoline 7,3'-indoline]trione. Up to 27 different spirooxindole derivatives were synthesized by this method. The bioactivity of these spirooxindole derivatives was evaluated and they were found to show antifungal activity against Cercospora arachidicola, Physalospora piricola, Rhizoctonia cerealis, and Fusarium moniliforme.
Subject(s)
Antifungal Agents , Benzopyrans , Indoles , Nitriles , Spiro Compounds , Water , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Water/chemistry , Indoles/chemistry , Indoles/pharmacology , Indoles/chemical synthesis , Microbial Sensitivity Tests , Oxindoles/pharmacology , Oxindoles/chemical synthesis , Oxindoles/chemistry , Molecular Structure , Structure-Activity Relationship , Fusarium/drug effectsABSTRACT
Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.
Subject(s)
Antineoplastic Agents , Cell Survival , Imatinib Mesylate , Oxindoles , Humans , K562 Cells , Imatinib Mesylate/pharmacology , Oxindoles/pharmacology , Oxindoles/chemical synthesis , Oxindoles/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Survival/drug effects , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Cell Proliferation/drug effects , Molecular Structure , Dose-Response Relationship, Drug , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/metabolism , Spiro Compounds/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/chemical synthesis , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Drug Screening Assays, AntitumorABSTRACT
A series of spiro ß-Lactams (4 a-c, 7 a-c) and thiazolidinones (5 a-c, 8 a-c) possessing 1,8-naphthyridine moiety were synthesized in this study. The structure of the newly synthesized compounds has been confirmed by IR, 1H-NMR, 13Câ NMR, mass spectra, and elemental analysis. The synthesized compounds were tested inâ vitro for their antibacterial and antifungal activity against various strains. The antimicrobial data showed that most of the compounds displayed good efficacy against both bacteria and fungi. The structure-activity relationship (SAR) studies suggested that the presence of electron-withdrawing chloro (3 b, 4 b, and 5 b) and nitro groups (7 b, 8 b) at the para position of the phenyl ring improved the antimicrobial activity of the compounds. The free radical scavenging assay showed that all the synthesized compounds exhibited significant antioxidant activity on DPPH. Compounds 8 b (IC50=17.68±0.76â µg/mL) and 4 c (IC50=18.53±0.52â µg/mL) showed the highest antioxidant activity compared to ascorbic acid (IC50=15.16±0.43â µg/mL). Molecular docking studies were also conducted to support the antimicrobial and SAR results.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents , Antioxidants , DNA Topoisomerases, Type II , Drug Design , Fungi , Microbial Sensitivity Tests , Naphthyridines , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Antioxidants/pharmacology , Antioxidants/chemical synthesis , Antioxidants/chemistry , Bacteria/drug effects , beta-Lactams/chemical synthesis , beta-Lactams/chemistry , beta-Lactams/pharmacology , Biphenyl Compounds/antagonists & inhibitors , DNA Topoisomerases, Type II/metabolism , Fungi/drug effects , Molecular Docking Simulation , Molecular Structure , Naphthyridines/pharmacology , Naphthyridines/chemistry , Naphthyridines/chemical synthesis , Picrates/antagonists & inhibitors , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemistry , Topoisomerase II Inhibitors/chemical synthesis , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacologyABSTRACT
Among the many neglected tropical diseases, leishmaniasis ranks second in mortality rate and prevalence. In a previous study, acridine derivatives were synthesized and tested for their antileishmanial activity against L. chagasi. The most active compound identified in that study (1) showed a single digit IC50 value against the parasite (1.10â µg/mL), but its macromolecular target remained unknown. Aiming to overcome this limitation, this work exploited inverse virtual screening to identify compound 1's putative molecular mechanism of action. In vitro assays confirmed that compound 1 binds to Leishmania chagasi pteridine reductase 1 (LcPTR1), with moderate affinity (Kd=33,1â µM), according to differential scanning fluorimetry assay. Molecular dynamics simulations confirm the stability of LcPTR1-compound 1 complex, supporting a competitive mechanism of action. Therefore, the workflow presented in this work successfully identified PTR1 as a macromolecular target for compound 1, allowing the designing of novel potent antileishmanial compounds.
Subject(s)
Acridines , Enzyme Inhibitors , Oxidoreductases , Oxidoreductases/antagonists & inhibitors , Oxidoreductases/metabolism , Acridines/chemistry , Acridines/pharmacology , Acridines/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/chemical synthesis , Molecular Dynamics Simulation , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Spiro Compounds/chemical synthesis , Structure-Activity Relationship , Molecular Structure , Parasitic Sensitivity Tests , Dose-Response Relationship, Drug , Leishmania/drug effects , Leishmania/enzymology , Molecular Docking SimulationABSTRACT
A series of spirocyclopropyl oxindoles with benzimidazole substitutions was synthesized and tested for their cytotoxicity against selected human cancer cells. Most of the molecules exhibited significant antiproliferative activity with compound 12 p being the most potent. It exhibited significant cytotoxicity against MCF-7 breast cancer cells (IC50 value 3.14±0.50â µM), evidenced by the decrease in viable cells and increased apoptotic features during phase contrast microscopy, such as AO/EB, DAPI and DCFDA staining studies. Compound 12 p also inhibited cell migration in wound healing assay. Anticancer potential of 12 p was proved by the inhibition of tubulin polymerization with IC50 of 5.64±0.15â µM. These results imply the potential of benzimidazole substituted spirocyclopropyl oxindoles, notably 12 p, as cytotoxic agent for the treatment of breast cancer.